High density lipoprotein (HDL) plays a critical role in preventing CVD. Inflammation is of[unreadable] central importance in the pathogenesis of atherosclerosis. Chronic inflammation leads to changes[unreadable] in HDL [e.g. decreased apolipoprotein A-l (apo A-l) and paraoxonase (PON1), and increased SAA[unreadable] and other novel proteins identified by mass spectrometry]. These changes are associated with a[unreadable] loss of its atheroprotective properties. Inflammation also may lead to pro-atherogenic changes in[unreadable] HDL. We hypothesize that compositional and functional changes in HDL induced by inflammation[unreadable] provides an important link between inflammation and atherosclerosis. We also hypothesize that[unreadable] changes in HDL composition may be biomarkers that indicate the presence of oxidative damage[unreadable] and/or atherosclerosis at the level of the artery wall. To test these hypotheses, we plan to[unreadable] determine how inflammation (acute and chronic) influences HDL composition, function and role in[unreadable] atherogenesis in mice. Next, we will test the mechanism by which inflammation reduces the[unreadable] atheroprotective HDL apolipoproteins apo A-l and PON1, and increases the potentially proatherogenic[unreadable] apolipoprotein SAA in HDL. Third, we will determine whether local over-expression by[unreadable] macrophages of inflammatory and anti-inflammatory proteins present in HDL affects the initiation[unreadable] and/or progression of atherosclerosis in a mouse model of hypercholesterolemia. Finally, we will[unreadable] determine whether chronic inflammation alters the composition and functional properties of HDL in[unreadable] humans in a manner similar to that in mice, and whether changes in HDL protein composition are[unreadable] markers of oxidation and/or atherosclerosis Many of these studies will involve the use of novel[unreadable] mass spectrometric approaches. These studies should provide important information to our longterm[unreadable] goal of understanding the relationship between inflammation, lipoprotein metabolism and[unreadable] atherosclerosis.